Tumor-secreted BDNF selectively depletes macrophage NAD+ via CD73 upregulation to suppress antitumor immunity

Tumor-secreted BDNF selectively depletes macrophage NAD+ via CD73 upregulation to suppress antitumor immunity | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Tumor-secreted BDNF selectively depletes macrophage NAD + via CD73 upregulation to suppress antitumor immunity Min Huang, Ting Wang, Guoqiang Dong, Zihan Zhang, Shuqian Hu, and 19 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8952568/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted You are reading this latest preprint version Abstract Intracellular nicotinamide adenine dinucleotide (NAD+) plays a pivotal role in linking cellular metabolic states to immune cell function, positioning NAD+ boosting as a promising immunotherapy strategy. However, whether a targetable NAD+ metabolic vulnerability exists within the tumor immune microenvironment remains poorly understood. Herein, we discover a novel metabolic crosstalk between tumor cells and macrophages that leads to specific NAD+ depletion in M1-like macrophages, resulting in a metabolic vulnerability that can be therapeutically exploited to enhance antitumor immunity. We demonstrate that brain-derived neurotrophic factor (BDNF) secreted by tumor cells upregulates CD73 expression in macrophages. By coupling to CD38 in M1-like macrophages, CD73 mediates selective intracellular NAD+ depletion, inducing a senescence associated secretory phenotype (SASP) that facilitates tumor immune evasion. Pharmacological activation of nicotinamide phosphoribosyltransferase (NAMPT) restores NAD+ levels in M1-like macrophages and sensitizes tumors to programmed cell death 1 receptor (PD-1) blockade. Importantly, NAMPT activator confines NAD+ elevation to M1-like macrophages, avoiding the systemic effects associated with the NAD+ precursor NMN supplementation. Together, our findings reveal a previously unrecognized tumor-macrophage interplay mediated by the BDNF-CD73 axis in reprogramming NAD+ metabolism and highlight NAMPT activation as a specific NAD+ boosting strategy to reinvigorate antitumor immunity. Biological sciences/Cancer/Cancer metabolism Biological sciences/Cancer/Cancer microenvironment Biological sciences/Cancer/Tumour immunology/Immunosurveillance/Immunoediting Biological sciences/Drug discovery/Target validation NAD+ BDNF CD73 CD38 NAMPT activator NMN M1-like macrophages SASP metabolic vulnerability immunotherapy Full Text Additional Declarations Yes there is potential Competing Interest. C.S. and G.D. have filed a patent application related to the development and therapeutic use of YB8 as a novel NAMPT activator. Supplementary Files Supplementaryinformation.pdf Supplementary methods ExtendedData.pdf Supplementary figure 1-6 Cite Share Download PDF Status: Under Review Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8952568","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":600414335,"identity":"a54920b7-c215-4708-88fc-1198d84afeea","order_by":0,"name":"Min 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